Biomedical subjects

H G Müller

Publications and source records attributed to H G Müller.

At least 19 recordsLinked to original sources

PubMed2001

Event history graphs for censored survival data.

A compact graphical device for combining survival and time-varying covariate information is proposed. The proposed graph contains the Kaplan-Meier estimator for right-censored data and a simultaneous display of the behaviour of time-dependent covariate(s) and the lifetime for each subject in the sample. The observed levels of time-dependent covariates are possibly subjected to an initial dimension reduction or smoothing step to produce a continuous covariate function. Values of this function are plotted on a horizontal bar for the length of the lifetime of the subject. Covariate information for censored data is also incorporated. The union of the horizontal bars forms the Kaplan-Meier estimator of the survival function. Our graphical method is implemented with a new S-plus function and demonstrated in several applications.

Age Factors↗

PubMed2001

Reproductive potential predicts longevity of female Mediterranean fruitflies.

Reproduction exacts a price in terms of decreased survival. Our analysis of the interplay between age patterns of fecundity and mortality for individual female medflies (Ceratitis capitata) revealed that individual mortality is associated with the time-dynamics of the egg-laying trajectory. In a sample of 531 medflies, we found that each individual has a characteristic rate of decline in egg laying with age. This defines an individual's rate of reproductive exhaustion. This rate was shown to predict subsequent mortality The larger the remaining reproductive potential, the lower the subsequent mortality An increased mortality risk was seen in flies for which egg production declined rapidly early on, irrespective of the level of egg production. Thus, reproductive potential and lifetime are coupled in such a way that those flies which are able to profit most from an extended life span in terms of increased egg output are indeed likely to live longer.

Animals↗

PubMed2001

Levels of alpha1 acid glycoprotein and ceruloplasmin predict future albumin levels in hemodialysis patients.

BACKGROUND: Serum albumin concentration predicts mortality in hemodialysis (HD) patients. While serum albumin concentration correlates with serum concentration of C-reactive protein (CRP) and is dependent upon CRP in multiple regression models in cross sectional studies, CRP does not predict future albumin levels, possibly because CRP changes rapidly, yielding large month-to-month variability in CRP. If inflammation causes rather than is simply associated with hypoalbuminemia, then changes in the levels of acute phase proteins should precede changes in serum albumin concentration. METHODS: The levels of long-lived positive and negative acute-phase proteins (APPs) (C-reactive protein, ceruloplasmin, alpha1 acid glycoprotein, transferrin and albumin) were measured longitudinally in 64 HD patients and a regression model was constructed to predict future albumin levels. Normalized protein catabolic rate (nPCR) was measured monthly. The number of repeated measurements ranged from 9 to 39 in each patient (median 22 and a mean of 23 measurements). To construct a model that would predict serum albumin concentration at any time j, values of all longitudinally measured APPs, positive and negative at any time j - 1, approximately 30 days prior to time j, were used. Other demographic factors (such as, race, access type, and cause of renal failure) also were incorporated into the model. RESULTS: The model with the best fit for predicting serum albumin at time j included albumin, ceruloplasmin, and alpha1 acid glycoprotein measured at time j - 1. The only demographic variable with subsequent predictive value was diabetes. CONCLUSIONS: The finding that changes in the concentration of the long lived APPs measured one month earlier are associated with predictable changes in the future concentration of serum albumin suggest that changes in inflammation are likely to be causal in determining serum albumin concentration in hemodialysis patients.

Adult↗

PubMed2001

Female sensitivity to diet and irradiation treatments underlies sex-mortality differentials in the Mediterranean fruit fly.

Large-scale experiments on medflies that were subjected to sterilizing doses of ionizing radiation (plus intact controls) and maintained on either sugar-only or full, protein-enriched diets revealed that, whereas the mortality trajectories of both intact and irradiated male cohorts maintained on both diets are similar, the mortality patterns of females are highly variable. Mean mortality rates at 35 days in male cohorts ranged from 0.2 to 0.3 but in female cohorts ranged from 0.09 to 0.35, depending on treatment. The study reports three main influences: (a) qualitative differences exist in the sex-mortality response of medflies subjected to dietary manipulations and irradiation; (b) the female mortality response is linked to increased vulnerability due to the nutritional demands of reproduction; and (c) female sensitivity to environmental changes underlies the dynamics of the sex-mortality differential.

Animals↗

PubMed2000

Pretransplant systemic inflammation and acute rejection after renal transplantation.

BACKGROUND: There are presently no established pre-transplant tests that consistently identify patients who may be at increased risk for acute rejection episodes after renal transplantation. We studied whether pretransplant serum levels of C-reactive protein (CRP), a marker for the presence of systemic inflammation, would predict the occurrence of acute rejection episodes after renal transplantation. METHODS: Pretransplant serum was tested for CRP level in 97 consecutive renal transplant recipients. Time to acute rejection after transplantation was stratified by CRP level and compared using the Kaplan-Meier method. In addition, Cox regression multivariate analysis was performed to assess whether any pretransplant covariates could independently predict the subsequent occurrence of acute rejection episodes. RESULTS: Pretransplant mean CRP levels were higher in patients who subsequently had a rejection episode versus those who had no rejection (22.2+/-2.9 vs. 11.7+/-1.8 microg/ml, respectively, P=0.003). Patients less than the median CRP value had a significantly longer time to rejection compared to those with higher CRP levels (P=0.002). Similarly, patients within the lowest CRP quartile had longer times to rejection when compared with the highest quartile (P=0.006). Cox proportional hazards regression multivariate analysis identified CRP level as the only independent pretransplant risk factor for rejection identified (P=0.044). CONCLUSIONS: Pretransplant systemic inflammation as manifested by elevated serum CRP level independently predicts the risk of acute rejection after renal transplantation and may be useful in stratifying patients at the time of transplantation according to immunological risk. Thus, assessment of pretransplant systemic inflammatory status may be helpful in prospective individualization of immunosuppression therapy after renal transplantation.

Acute Disease↗

PubMed2000

A change-point model for reporting delays under change of AIDS case definition.

Accurate monitoring of disease incidence is of major public health concern. The time delay between diagnosis and the date of reporting creates bias in estimating disease incidence. Changes in case definition are expected to have an impact on the time lag of case reporting. We propose a change-point model for reporting delays in AIDS that takes into account recent changes in the AIDS definition in US and European countries. The model was applied to California AIDS surveillance data and the distribution of reporting delays before and after the recent change of definition in 1993 were analyzed in terms of contributing factors. The overall significance of the model with change-point as compared to the model without change-point indicates that the effect of the 1993 change in definition on the distribution of reporting delays was highly significant (p < 0.0001). Overall, reporting delay of cases initially diagnosed with AIDS-defining diseases before 1993 was shorter compared to after 1993; reporting delay of cases initially diagnosed meeting the 1993 immunologic case definition was shorter than of those initially diagnosed with AIDS-defining diseases. Region of residence, mode of exposure, race/ethnicity and time of diagnosis emerged as the main covariates in the models. The method introduced here applies to current and possible future changes of the AIDS case definition as well as changes in diagnostic criteria or case definition in diseases other than AIDS. We demonstrate that such changes may be accompanied by sizeable changes in the distribution of reporting delays, and thus adjustment for reporting delays must be recalibrated after a change in definition.

Acquired Immunodeficiency Syndrome↗

PubMed2000

The acute-phase response varies with time and predicts serum albumin levels in hemodialysis patients. The HEMO Study Group.

BACKGROUND: Cross sectional studies have established that the serum albumin level is dependent on serum levels of acute-phase proteins (APPs) or cytokine levels in hemodialysis patients. While the acute-phase response is generally associated with acute inflammatory events, a cross sectional analysis relating laboratory values to outcomes assumes these values to be unchanging. The longitudinal relationship among laboratory measurements and how they vary over time in a population of patients are unknown. METHODS: Patients who were enrolled in the HEMO Study were recruited into an ancillary longitudinal study to establish the predictive effect of temporal variation in the levels of APPs and of temporal variation in normalized protein catabolic rate (nPCR) on the serum albumin concentration. nPCR was measured monthly using a double-pool method. The positive APPs-C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1-AG), and ceruloplasmin-and the negative APP-transferrin (Trf)-were measured in serum obtained before each dialysis session for six weeks and then monthly in 37 hemodialysis patients. A random coefficient regression analysis was used to assess the association of serum albumin with other measured parameters at each time point, as well as fixed patient characteristics. RESULTS: The within-subject coefficients of variation of albumin (median, range of 25th to 75th percentiles; median, 0.0614; range, 0.0485 to 0.0690) were significantly less than that of APPs (CRP, median, 0.878; range, 0.595 to 1.314, P < 0. 05; and alpha1 AG, median, 0.173; range, 0.116 to 0.247, P < 0.05). The levels of APPs and albumin varied considerably over time. The primary predictor of current albumin was the current CRP level (P = 0.0014). nPCR also was a significant predictor for albumin levels (P = 0.0440) after controlling for the effect of APPs, suggesting an effect of nPCR on serum albumin concentration irrespective of the acute-phase response. Age and the presence of an arteriovenous graft were significant predictors that were associated with reduced albumin. CONCLUSIONS: The acute-phase response is intermittent and is not a continuous feature in individual dialysis patients. Levels of APPs are the most powerful predictors for the levels of albumin concentration in hemodialysis in a longitudinal setting. Since variations in albumin are small, measurement of variations in APPs may provide greater insight into the dynamics of clinically relevant processes.

Acute-Phase Reaction↗

PubMed1999

Mortality oscillations induced by periodic starvation alter sex-mortality differentials in Mediterranean fruit flies.

Sex-specific mortality rates of medflies were monitored in cages containing individuals of both sexes and with food (either sugar-only or full diet) removed every 2nd, 3rd, or 4th day (plus ad libitum controls). The general finding is that periodic starvation led to marked oscillations in raw mortality rates. The specific findings are as follows: (i) female medflies live longer than male medflies when they are subjected to periodic starvation; (ii) male medflies maintained on a full diet experience a catastrophic increase in mortality (40%) on the first day food is removed. This mortality surge was not observed for females on either diet or for males maintained on a sugar-only diet; (ii) life expectancy is inversely related to the amplitude of mortality oscillations caused by food deprivation; and (iv) the large perturbations in mortality at younger ages caused by periodic starvation has little effect on the amplitude of mortality at older ages. In general, our data shed new light on the complexity of the mortality response of medflies to both the type and availability of food and thus provide a complimentary perspective to findings from dietary restriction studies on both vertebrate and invertebrate systems.

Adaptation, Physiological↗

PubMed1998

Dual modes of aging in Mediterranean fruit fly females.

The life history of medflies is characterized by two physiological modes with different demographic schedules of fertility and survival: a waiting mode in which both mortality and reproduction are low and a reproductive mode in which mortality is very low at the onset of egg laying but accelerates as eggs are laid. Medflies stay in waiting mode when they are fed only sugar. When fed protein, a scarce resource in the wild, medflies switch to reproductive mode. Medflies that switch from waiting to reproductive mode survive longer than medflies kept in either mode exclusively. An understanding of the physiological shift that occurs between the waiting and reproductive modes may yield information about the fundamental processes that determine longevity.

Aging↗

PubMed1998

Statistical models for quantitative bioassay.

We discuss various statistical approaches useful in the analysis of nutritional dose-response data with a continuous response. The emphasis is on the multivariate case with several predictors. The methods which will be discussed can be classified into parametric models, including change-point models, and nonparametric models, which rely on smoothing methods such as weighted local linear fitting. The methods will be illustrated with the analysis of data generated from a folate depletion-repletion bioassay experiment conducted on rats, where the measured growth rate of the rate is the response variable. We also discuss the biological conclusions that can be drawn from applying various statistical methods to this data set.

Animal Nutritional Physiological Phenomena↗

PubMed1998

Statistical tools for the analysis of nutrition effects on the survival of cohorts.

We discuss various methods which can be employed for the comparative analysis of samples of response curves. In the application discussed here, these curves are hazard functions, each generated by the survival data obtained for a cohort of experimental subjects which are fed a specific diet. It is demonstrated how comparisons of the effects of different diets on survival can be carried out by employing statistical techniques for inference on samples of curves. The methods are illustrated with data on the survival of large cohorts of male and female Mediterranean fruit flies under full diet and under protein deprivation. These statistical methods allow one to investigate differences between the samples of hazard functions generated by the four groups defined by combinations of sex and diet.

Analysis of Variance↗

PubMed1998

Characterization of factor VIII/von Willebrand factor concentrates using a modified method of von Willebrand factor multimer analysis.

In order to provide patients with von Willebrand disease a factor VIII (FVIII)/von Willebrand factor (vWF) concentrate of reproducible quality, an SDS-agarose gel electrophoresis method has been established to determine the content of the high molecular weight multimers (band 11 and higher) of vWF. This method has been used to characterize the content of high molecular weight vWF multimers in Humate P/Haemate P, a commercial FVIII/vWF concentrate. The average content of high molecular weight vWF multimers of 47 batches of Humate P/Haemate P has been determined to be 84.1% of the corresponding bands in normal human plasma. Use of this multimer analysis method for the characterization of five further commercial products revealed clear differences with respect to the high molecular weight vWF multimer content. Furthermore, there is a linear correlation (r2 = 0.73) between the content of high molecular weight vWF multimers and the specific activity of vWF (determined as vWF:RCoF/vWF:Ag). The method described here for analysis of the content of high molecular weight vWF multimers is a reliable and reproducible method to characterize this class of factor concentrates with respect to vWF multimer composition.

Electrophoresis↗

PubMed1998

Comparative in vitro investigation of prothrombin complex concentrates.

Three commercial prothrombin complex concentrates (PCC) were compared in vitro. Differences in the activities or contents, respectively, of the PCC factors FII, FVII, FIX, FX and the proteins C, S, and Z (antigen) in particular were found. Global tests of activated factors did not reveal marked differences between the products. Neither free thrombin nor elevated levels of activated FX were detected. In contrast, analyses of FVIIa, of residual amidolytic activities, and of concentrations of unwanted ingredients demonstrated considerable differences between the products. While antithrombin III was detected only in two of three concentrates, heparin was found in all PCCs but in markedly different concentrations. Although the homogeneity of the products has been clearly improved in comparison with former comparative investigations, the products can be distinguished by their compound profile and by a couple of in vitro assays.

Biological Products↗

PubMed1998

Estimating the concentration of beta-carotene required for maximal protection of low-density lipoproteins in women.

The reportedly inconsistent antioxidant protective effect of beta-carotene on plasma LDL may depend on LDL's beta-carotene concentration. We measured carbonyl production by CuSO4-challenged LDL from nine healthy women living at the US Department of Agriculture-Western Human Nutrition Research Center and consuming a natural food diet that provided only 0.14 micromol beta-carotene/d for 120 d. During the first 60 d, four women received a placebo and the remaining five women received too small a supplement (0.93 micromol beta-carotene/d) to increase plasma or LDL beta-carotene; therefore, the data for all nine women during this time were pooled. From days 61 to 120, all subjects received the small supplement. From days 101 to 120 they all received an additional, larger, mixed carotenoid supplement (6.16 micromol beta-carotene/d). Plasma beta-carotene dropped from 0.76 +/- 0.21 micromol/L (x +/- SEM) on day 2 to 0.33 +/- 0.08 on day 60 (P = 0.035) and rose to 1.73 +/- 0.18 (P = 0.001) on day 120. LDL beta-carotene dropped from 1.67 +/- 0.53 micromol/g LDL protein on day 2 to 1.27 +/- 0.28 micromol/g LDL protein on day 60 (P = 0.650) and rose to 10.04 +/- 1.07 micromol/g LDL protein (P = 0.001) on day 120. Plasma lycopene dropped from 0.20 micromol/L on day 2 to 0.02 micromol/L on day 60 and did not increase by day 120. Carbonyl production rose from 24 +/- 6 micromol/g LDL protein on day 2 to 42 +/- 4 micromol/g LDL protein (P = 0.001) on day 60 and dropped to 6 +/- 1 micromol/g LDL protein (P = 0.001) on day 120. LDL seemed fully protected with 9.7 +/- 2.5 micromol beta-carotene/g LDL protein, or 2.3 +/- 1.8 micromol beta-carotene/L plasma.

Adolescent↗

PubMed1997

Early mortality surge in protein-deprived females causes reversal of sex differential of life expectancy in Mediterranean fruit flies.

Experiments based on over 400,000 medflies revealed that females maintained on a normal diet (sucrose plus protein) have a higher life expectancy than males maintained on a normal diet, with a difference of 1.30 +/- 0.27 days in favor of females. However, this sex differential reverses under protein deprivation, with a difference of 2.24 +/- 0.18 days in favor of males. The reversal of the male-female life expectancy differential is caused by a sustained surge in early female mortality under protein deprivation that is tied to egg-laying and physiological processes. In contrast, male mortality and life expectancy are only mildly affected by protein deprivation. The surge in early mortality for female medfly cohorts is an instance of a vulnerable period. These vulnerable periods are linked with patterns in hazard rates.

Aging↗

PubMed1996

Statistical interaction model for exchangeability of food folates in rat growth bioassay.

The comparative value of several sources of dietary folate in promoting growth of folate-depleted rats was determined in a folate depletion-repletion rat growth bioassay. Folate-depleted rats were fed an amino acid-based diet supplemented with 11 different concentrations of folate (227, 272, 317, 363, 408, 454, 499, 544, 590, 635 and 680 nmol/kg) from each of 12 different sources of folate (folic acid, fried beef liver, cooked pinto beans individually, or as 1/3, 1/1, or 3/1 combinations of folate from the folic acid/beans, folic acid/beef liver and beans/beef liver) for a total of 132 treatments. Growth response to folic acid and bean folate was linear, whereas that to beef liver folate was distinctly nonlinear, beef liver folate being more potent at lower dietary concentrations but less potent at higher concentrations compared with folic acid and bean folate. Folic acid and bean folate were equivalent to and exchangeable with one another in promoting growth. Beef liver folate and folic acid/bean folate had an interactive effect in promoting growth. The nature of the interaction was antagonistic in that the presence of folic acid and/or bean folate reduced the efficacy of beef liver folate and vice versa. Beef liver folate is not exchangeable with either folic acid or bean folate. We conclude that food folates generally are not exchangeable and do interact adversely. A statistical interaction model that predicted the growth-promoting effect of several sources of dietary folate was developed and validated.

Animals↗

PubMed1996

[Nanofiltration in production of Beriplex P/N: increasing the capacity of virus elimination while maintaining product quality].

For the manufacture of the PCC Beriplex P/N, nanofiltration was introduced into the production process of Beriplex HS providing an additional means to heat treatment for the clearance/inactivation of viruses. By nanofiltration, large enveloped viruses (HSV-1, HIV-1) were completely eliminated by a factor of more than 7 log10. While medium-sized enveloped viruses (HBV, BVDV) were cleared by a factor of approximately 4 log10, small non-enveloped viruses (poliovirus) were not removed. The product profile remained, no thrombogenic activities were detected.

Blood Coagulation Factors↗

PubMed1995

Estimating derivatives of pharmacokinetic response curves with varying bandwidths.

A kernel-smoothing method with locally varying bandwidths for the nonparametric estimation of derivatives of a function is proposed for highly nonequidistant data as they occur in pharmacokinetic response curves. We construct estimates having the particular property that the derivative estimates correspond exactly to the corresponding derivatives of the curve estimate even under locally varying bandwidth choice. The effects on the estimation of peak location (characteristic points) are investigated. In an example, characteristic points are estimated for a recently developed in vivo isotope dilution assay for vitamin A (retinol) nutritional status. The in vivo kinetics of appearance and disappearance of isotopically labeled retinol can be described with the proposed method.

Anticarcinogenic Agents↗